U.S. patent application number 10/192856 was filed with the patent office on 2003-04-10 for process for the production of peracylated 1-0-glycosides.
This patent application is currently assigned to Schering AG. Invention is credited to Graske, Klaus-Dieter, Niedballa, Ulrich, Platzek, Johannes.
Application Number | 20030069402 10/192856 |
Document ID | / |
Family ID | 27214511 |
Filed Date | 2003-04-10 |
United States Patent
Application |
20030069402 |
Kind Code |
A1 |
Platzek, Johannes ; et
al. |
April 10, 2003 |
Process for the production of peracylated 1-0-glycosides
Abstract
The invention relates to a process for the production of
peracylated 1-O-glycosides of general formula I or salts thereof 1
in which sugar is a monosaccharide that is functionalized in
1-OH-position, R represents methyl, ethyl, propyl, isopropyl,
tbutyl, phenyl, n means 2, 3 or 4, X means --COO-- or --NH--and L
means a straight-chain, branched, saturated or unsaturated
C.sub.1-C.sub.30 carbon chain, which optionally is interrupted or
substituted by groups. The process according to the invention
starts from economical starting materials, provides good yields and
allows the production of peracylated saccharides with
1-O-functionalized side chains on an enlarged scale.
Inventors: |
Platzek, Johannes; (Berlin,
DE) ; Graske, Klaus-Dieter; (Berlin, DE) ;
Niedballa, Ulrich; (Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
Schering AG
Berlin
DE
|
Family ID: |
27214511 |
Appl. No.: |
10/192856 |
Filed: |
July 11, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60305876 |
Jul 18, 2001 |
|
|
|
Current U.S.
Class: |
536/18.7 ;
536/110; 536/17.4; 536/23.1 |
Current CPC
Class: |
C07H 15/18 20130101;
C07H 15/26 20130101; C07H 15/04 20130101 |
Class at
Publication: |
536/18.7 ;
536/110; 536/17.4; 536/23.1 |
International
Class: |
C07H 021/02; C07H
021/04; C08B 037/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 11, 2001 |
DE |
101 350 98.8 |
Claims
1. Process for the production of peracylated 1-O-glycosides of
general formula I 5in which sugar.sup.1 is a monosaccharide that is
functionalized in 1-OH-position, R represents methyl, ethyl,
propyl, isopropyl, tbutyl, phenyl, n means 2, 3 or 4, X means
--COO-- or --NH--and L means a straight-chain, branched, saturated
or unsaturated C.sub.1-C.sub.30 carbon chain, which optionally is
interrupted by 1-10 oxygen atoms, 1-3 sulfur atoms, 1-2 phenylene
groups, 1-2 phenylenoxy groups, 1-2 phenylenedioxy groups, a
thiophene radical, pyrimidine radical or pyridine radical, and/or
optionally is substituted with 1-3 phenyl groups, 1-3 carboxyl
groups, 1-5 hydroxy groups, 1-5 O-C.sub.1-C.sub.7 alkyl groups, 1-3
amino groups, 1-3 CF.sub.3 groups or 1-10 fluorine atoms or their
salts, characterized in that a peracylated 1-OH-sugar of general
formula II 6in which sugar.sup.1, R and n have the indicated
meaning, is reacted with an alkylating reagent of general formula
(III) Nu-L-X-Sg (III), in which Nu means a nucleofuge, L and X have
the above-mentioned meaning, and Sg represents a protective group,
in an organic solvent in the presence of a base and optionally a
phase transfer catalyst at a temperature of 0-50.degree. C., then
the protective group is cleaved off, and the reaction product that
is obtained is optionally converted into a salt.
2. Process according to claim 1, wherein a peracylated
monosaccharide with 5 to 6 C-atoms or its deoxy compound is used as
a peracylated 1-OH-sugar of general formula II.
3. Process according to claim 1 or 2, wherein peracylated glucose,
mannose, galactose, ribose, arabinose, xylose, fucose or rhamnose
is used as a peracylated 1-OH-sugar of general formula II.
4. Process according to one of claims 1 to 3, wherein as an
alkylating reagent of general formula III, one is used in which the
nucleofuge means radicals --Cl, --Br, --I, --OTs, --OMs,
--OSO.sub.2CF.sub.3, --OSO.sub.2C.sub.4F.sub.9 or
--OSO.sub.2C.sub.8F.sub.17.
5. Process according to one of claims 1 to 4, wherein as an
alkylating reagent of general formula III, one is used in which
radical L means 7whereby .gamma. is the interface site to sugar,
and .delta. is the interface site to radical X.
6. Process according to one of claims 1 to 5, wherein as an organic
solvent, dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl
ether, diethoxymethane, tetrahydrofuran, acetonitrile, formamide,
dimethylformamide, dimethylacetamide, benzene, toluene,
CF.sub.3-benzene, hexane, cyclohexane, diethyl ether,
dichloromethane, methyl-t-butyl ether (MTB), dimethyl sulfoxide,
sulfolane or a mixture thereof is used.
7. Process according to one of claims 1 to 6, wherein a quaternary
ammonium or phosphonium salt or a crown ether, preferably a
quaternary ammonium salt, is used as a phase transfer catalyst.
8. Process according to one of claims 1 to 7, wherein potassium
carbonate, sodium carbonate, cesium carbonate,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-oc-
tane (DABCO), potassium-t-butoxide, sodium-t-butoxide or a mixture
of cesium carbonate and potassium carbonate or sodium carbonate is
used as a base.
9. Process according to one of claims 1 to 7, wherein the base is
added in solid or liquid form.
10. Compounds according to claim 1:
Carboxymethyl-2,3,4,6-tetra-O-acetyl-m- annopyranose
Carboxymethyl-2,3,4,6-tetra-O-pivaloyl-mannopyranose
Carboxymethyl-2,3,4,6-tetra-O-benzoyl-mannopyranose.
Description
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application Serial No. 60/305,876 filed Jul. 18,
2001.
DESCRIPTION
[0002] The invention relates to a new process for the production of
peracylated 1-O-glycosides of general formula I, which is cited in
more detail in the claims. The process according to the invention
starts from economical starting materials, provides good yields,
and allows the production of peracylated saccharides with
1-O-functionalized side chains on an enlarged scale.
[0003] Peracylated saccharide derivatives are valuable intermediate
products in synthetic chemistry. Pharmaceutical chemistry primarily
uses such components very frequently, since many highly potent and
selective pharmaceutical agents carry sugar radicals. Thus, for
example, in the Journal of Drug Targeting 1995, Vol. 3, pp.
111-127, applications of the so-called "glycotargeting" are
described. So-called "multi-antennary sugar chains" are described
in Chemistry Letters 1998, p. 823. By clustering sugar units, the
carbohydrate-receptor-interaction in the case of the
cell-cell-interaction is considerably improved. The synthesis of
galactosides with high affinity to the asialoglycoprotein receptor
was published in J. Med. Chem. 1995, 38, p. 1538 (see also Int. J.
Peptide Protein Res. 43, 1994, p. 477). Here, derivatized
galactoses with functionalized side chains are produced, which then
can be suspended on various other molecules. A good survey on the
use of saccharides as a basis of glycobiology was provided in Acc.
Chem. Res. 1995, 321. Also, for the synthesis of LewisX mimetic
agents (Tet. Lett. Vol. 31, 5503), functionalized monosaccharides
are used as precursors (see also JACS 1996, 118, 6826).
[0004] The use of derivatized monosaccharides as intermediate
stages for potential pharmaceutical agents was well represented in
Current Medicinal Chemistry, 1995, 1, 392. Perbenzylated-1-OH-sugar
derivatives (galactose, glucose) are also used in the synthesis of
heart-active glycosides (digitoxin-conjugates). The
1-O-glycosylation is carried out here via trichloroacetimidate and
BF.sub.3-catalysis (J. Med. Chem. 1986, 29, p. 1945). For the
production of immobilized sugar ligands (e.g., linkage to HSA),
functionalized, protected monosaccharides are used (Chemical
Society Reviews 1995, p. 413).
[0005] It is the purpose of a group of syntheses to introduce
additional functionality into a sugar molecule via a
1-O-glycosylation reaction. Here, primarily terminal COOH--, amino-
or OH-- groups are of interest, since the latter can be further
reacted in subsequent steps.
[0006] The production of 1-O-glycosides is carried out in most
cases according to standard methods, such as, e.g., according to
the trichloroacetimidate methods described by Koenigs-Knorr,
Helferich or by R. R. Schmidt [W. Koenigs and E. Knorr, Ber. dtsch.
chem. Ges. 34 (1901) 957; B. Helferich and J. Goendeler, Ber.
dtsch. Chem. Ges. 73, (1940) 532; B. Helferich, W. Piel and F.
Eckstein, Chem. Ber. 94 (1961), 491; B. Helferich and W. M. Muller,
Chem. Ber. 1970, 103, 3350; G. Wulff, G. Rohle and W. Kruger, Ang.
Chem. Internat. Edn., 1970, 9, 455; J. M. Berry and G. G. S.
Duthon, Canad. J. Chem. 1972, 50, 1424; R. R. Schmidt, Angew. Chem.
[Applied Chemistry] 1986, 98, 213.]
[0007] A feature that is common to all of these methods is that the
1-hydroxyl group is converted into a reactive form that is
ultimately used as a leaving group. Under Lewis acid catalysis
(partially in stoichiometric amount), the actual reaction is
carried out with an alcohol to form 1-O-glycoside. For such
reactions, numerous examples are provided in the literature.
[0008] In the production of immunostimulant KRN-7000 (Kirin
Brewery), the condensation of
tetra-O-benzyl-.beta.-D-galactopyranosyl-bromide with a primary
alcohol, whose hydroxyl group sits at the end of a
di-hydroxy-amido-C-chain (in DMF/toluene under Lewis acid
catalysis), is thus a central step (Drug of the Future 1997, 22(2),
p. 185). In Japanese Patent JP 95-51764, the reaction of
1-O-acetyl-2,3,4-tri-O-benzyl-L-fucop- yranose with
polyoxyethylene-30-phytosterol (BPS-30, NIKKO Chem., Japan) under
trimethyl-silylbromide/zinc triflate catalysis was described. In
Bull. Chem. Soc. 1982, 55(4), pp. 1092-6,1-O-glycosylations of
perbenzyl-sugars under titanium tetrachloride catalysis in
dichloromethane are described.
[0009] In Liebigs Ann. Org. Bioorg. Chem.; EN; 9; 1995; 1673-1680,
the production of
3,4,5-trisbenzyloxy-2-benzyloxymethyl-6-(2-hexadecyloxyetho-
xy)-tetrahydropyran is described. Starting from
2,3,4,6-tetra-O-benzyl-D-g- lucopyranose, the 1-O-glycosylation is
performed with use of Bu.sub.4NBr, CoBr.sub.2, Me.sub.3SiBr and a
molecular sieve in methylene chloride within 60 hours.
[0010] A tetrabenzyl derivative, which contains a terminal carboxyl
group that is protected as a methyl ester, is described in
Carbohydr. Res.; EN; 230; 1; 1992; 117. The carboxyl group can then
be released and further reacted. For glycosylation, silver
carbonate is used in dichloromethane. The use of expensive silver
carbonate limits the batch size and makes an economical up-scaling
almost impossible. The same problem applies for the compound below,
which was described in Tetrahedron Lett. 30, 44, 1989, p. 6019.
Here, 2,3,4,6-tetra-O-benzyl-D-mannosyl-bromide in nitromethane is
reacted with 2-benzyloxyethanol with the aid of mercury cyanide to
form 1-O-glycoside. The use of mercury cyanide in pilot-plant
installations is problematical in nature and can be rejected from
the environmental-political standpoint.
[0011] The substance libraries for the high-capacity-screening
described most recently very frequently use saccharides (Angew.
Chemie 1995, 107, 2912). Here, the purpose is to have present sugar
components in protected form, which carry a functional group, such
as, e.g., --COOH, or --NH.sub.2, which can be reacted in, e.g., an
automated synthesis. The components that are used in this respect
were described by Lockhoff, Angew. Chem. 1998, 110 (24), p. 3634.
Primarily the 1-O-acetic acid of perbenzyl-glucose is important
here. The production is carried out over two stages, via
trichloroacetimidate and reaction with hydroxyacetic acid ethyl
ester, BF.sub.3 catalysis in THF and subsequent saponification with
NaOH in MeOH/THF. The total yield over two stages is only 59%,
however.
[0012] In the same publication, the production of a
1-O-(aminoethyl)-glycoside of the perbenzylated glucose is also
described. The reaction is carried out, also starting from
trichloroacetimidate, by reaction with N-formylaminoethanol under
BF3-catalysis in THF and subsequent saponification in MeOH/THF. The
total yield is also relatively low here; it is 45%.
[0013] A 1-O-(aminoethyl) derivative of perbenzylxylose passes
through as an intermediate product in Carbohydrate Research 1997,
298, p. 173. The synthesis is very lengthy, however, since it
starts from 1-bromo-peracetate of xylose. The actual
1-O-glycosylation is carried out via a 1-phenylthioether, which is
reacted with 2-azidoethanol under DMTST catalysis (=dimethyl
(methylthio)-sulfonium-triflate) in dichloromethane (total number
of stages: 7). The total yield is not suitable for an industrial
application with less than 40%.
[0014] In the survey article by R. R. Schmidt in Angew. Chem. 1986,
98, pp. 213-236, direct reactions of 1-OH-perbenzyl-glucose and
-ribose with 2-haloesters and triflates are described. As a base,
sodium hydride in THF or benzene is used (Chem. Ber. 1982, 115);
the yields are between 40 and 55%. The use of sodium hydride in
dioxane or potassium-tert-butylate in THF (both at room
temperature) is also described for 1-O-alkylation with triflates
(Angew. Chem. 1986, 98, p. 218). The anhydrous reaction conditions
that are to be followed most strictly represent a large hurdle in
up-scaling such alkylations.
[0015] All processes known to date have the great disadvantage that
an up-scaling of the process cannot be achieved easily. The use of
Lewis acids in 1-O-glycosylation as well as sodium hydride in
1-O-alkylation already requires anhydrous reaction conditions,
which in large batches is always associated with difficulties. The
working-up and disposal of reaction adjuvants (Hg/cyanide/etc.) is
also a problem in many cases.
[0016] The object of the invention was therefore to provide a
process with which peracylated saccharides with 1-O-functionalized
side chains can be produced at a reasonable price and in an
ecologically beneficial way on an enlarged scale.
[0017] The object of the invention is achieved according to the
process that is indicated in the claims, with which peracylated
1-O-glycosides of general formula I 2
[0018] can be produced. According to the definition of the
invention, sugar.sup.1 in general formula I means a monosaccharide
that is functionalized in 1-OH position, whereby in this
connection, it can also be a deoxy sugar, which contains an H-atom
instead of one or more OH groups. In a preferred embodiment of the
invention, the sugar in general formula I means a monosaccharide
with 5 or 6 C atoms, e.g., glucose, mannose, galactose, ribose,
arabinose or xylose or deoxy sugars thereof, such as, for example,
6-deoxygalactose (fucose) or 6-deoxy-mannose (rhamnose).
[0019] Radical --COR represents the acyl group that is present in
at least two places based on the monosaccharide that is used or its
deoxy form, and is present accordingly in several places with use
of di-, tri- or polysaccharides. As radicals R, aliphatic and
aromatic groups, such as, for example, methyl, ethyl, isopropyl,
t-butyl or phenyl are considered.
[0020] Radical X means --COO-- or --NH--. In the result of the
process according to the invention, alcohols, carboxylic acids, or
amines of general formula I are thus obtained.
[0021] Radical L can mean a straight-chain, branched, saturated, or
unsaturated C.sub.1-C.sub.30-carbon chain, which optionally is
interrupted by 1-10 oxygen atoms, 1-3 sulfur atoms; 1-2 phenylene
groups, 1-2 phenylenoxy groups, 1-2 phenylenedioxy groups; a
thiophene radical, pyrimidine radical or pyridine radical; and/or
optionally is substituted with 1-3 phenyl groups, 1-3 carboxyl
groups, 1-5 hydroxy groups, 1-5 O-C.sub.1-C.sub.7 alkyl groups, or
1-3 amino groups; 1-3 CF.sub.3 groups, or 1-10 fluorine atoms. In
terms of the invention, preferred radicals L are 3
[0022] whereby .gamma. means the interface site to the sugar, and
.delta. is the interface site to radical X. An especially preferred
linker L is the --CH.sub.2 group.
[0023] For the production of peracylated 1-O-glycosides of general
formula I, a peracylated 1-OH sugar of general formula II 4
[0024] in which sugar, R and n have the above-indicated meaning, is
dissolved in an organic solvent and reacted with an alkylating
reagent of general formula III
Nu-L-X-Sg (III),
[0025] in which Nu means a nucleofuge, L and X have the
above-mentioned meaning, and Sg is a protective group, in the
presence of a base and optionally a phase transfer catalyst. As a
nucleofuge, for example, the radicals --Cl, --Br, --I, --OTs,
--OMs, --OSO.sub.2CF.sub.3, --OSO.sub.2C.sub.4F.sub.9 or
--OSO.sub.2C.sub.8F.sub.17 can be contained in the alkylating
reagent of general formula III.
[0026] Protective group Sg is a common acid or amine protective
group, depending on whether X means the radical --COO-- or --NH--.
These protective groups are well known to one skilled in the art
(Protective Groups in Organic Syntheses, Second Edition, T. W.
Greene and P. G. M. Wuts, John Wiley & Sons, Inc., New York
1991).
[0027] The reaction according to the invention can be carried out
at temperatures of 0-50.degree. C., preferably 0.degree. C. to room
temperature. The reaction times are 10 minutes to 24 hours,
preferably 20 minutes to 12 hours.
[0028] The base is added either in solid form, preferably in
fine-powder or liquid form. Cesium carbonate, potassium carbonate,
1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU),
1,5-diazabicyclo-[2.2.2]octane (DBN),
1,4-diaza-bicyclo[2.2.2]octane (DABCO), potassium-t-butoxide and
sodium-t-butoxide, sodium carbonate, or a mixture that consists of
cesium carbonate and potassium carbonate or sodium carbonate are
used as preferred bases.
[0029] As organic solvents, for example, acetonitrile, dioxane,
tetrahydrofuran, diethoxymethane, 1,2-dimethoxyethane, diethylene
glycol dimethyl ether, benzene, formamide, hexane, toluene,
dimethylformamide, dimethylacetamide, cyclohexane, CF3-benzene,
diethyl ether, dichloromethane, methyl-t-butyl ether (MTB),
dimethyl sulfoxide, sulfolane or mixtures thereof can be used in
the alkylating process according to the invention.
[0030] As phase transfer catalysts, the quaternary ammonium or
phosphonium salts that are known for this purpose or else crown
ethers, such as, e.g., [15]-crown 5 or [18]-crown 6, are used in
the process according to the invention. Preferably quaternary
ammonium salts with four hydrocarbon groups that are the same or
different on the cation, selected from methyl, ethyl, propyl,
isopropyl, butyl or isobutyl, are suitable. The hydrocarbon groups
on the cation must be large enough to ensure good solubility of the
alkylating reagent in the organic solvent. According to the
invention, N(butyl).sub.4.sup.+-Cl.sup.-, or
N(butyl).sub.4.sup.+-HSO- .sub.4.sup.-, but also
N(methyl).sub.4.sup.+-Cl.sup.- is especially preferably used.
[0031] After the reaction is completed, the working-up of the
reaction mixture can be carried out by isolation of the still
protected end product and subsequent usual cleavage of the
protective group to the end product of general formula I. It is
preferred, however, not to isolate the still protected end product
but rather to remove the solvent, to take up the residue in a new
solvent that is suitable for the cleavage of the protective group
and to perform the cleavage here. The procedure for cleavage of the
protective group and for regeneration of the acid, amino or hydroxy
group is well known to one skilled in the art.
[0032] If, for example, protective group Sg is an acid protective
group that blocks the acid proton of the carboxy group, thus, e.g.,
methyl, ethyl, benzyl or tert-butyl, the acid is usually
regenerated by alkaline hydrolysis. In the process of the
invention, however, the alcoholic hydroxyl groups are also
protected as esters. As a protective group for the carboxylic acid
in addition to the allyl group and silyl group, the benzyl group is
available. This protective group can be easily removed by catalytic
hydrogenation. As a catalyst, in this case palladium (10%) on
activated carbon has proven to be effective.
[0033] As hydroxy protective groups (in L), e.g., benzyl,
4-methoxybenzyl, 4-nitrobenzyl, trityl, diphenylmethyl,
trimethylsilyl, dimethyl-tert-butylsilyl, or
diphenyl-tert-butylsilyl groups are suitable.
[0034] The hydroxy groups can also be present, e.g., as THP-ethers,
.alpha.-alkoxyethylethers, MEM-ethers or as esters with aromatic or
aliphatic carboxylic acids, such as, e.g., acetic acid or benzoic
acid. In the case of polyols, the hydroxy groups can also be
protected in the form of ketals with, e.g., acetone, acetaldehyde,
cyclohexanone or benzaldehyde.
[0035] The hydroxy protective groups can be released according to
the literature methods that are known to one skilled in the art,
e.g., by hydrogenolysis, acid treatment of ethers and ketals,
alkali treatment of esters or treatment of silyl protective groups
with fluoride (see, e.g., Protective Groups in Organic Syntheses,
Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley &
Sons, Inc., New York, 1991).
[0036] The NH.sub.2 groups can be protected and released again in a
variety of ways. The N-trifluoroacetyl derivative is cleaved by
potassium or sodium carbonate in water [H. Newman, J. Org. Chem.,
30:287 (1965), M. A. Schwartz et al., J. Am. Chem. Soc., 95 G12
(1973)] or simply by ammonia solution [M. Imazama and F. Eckstein,
J. Org. Chem., 44:2039 (1979)]. The tert-butyloxycarbonyl
derivative is equally easy to cleave: stirring with trifluoroacetic
acid suffices [B. F. Lundt et al., J. Org. Chem., 43:2285 (1978)].
The group of NH.sub.2-protective groups to be cleaved
hydrogenolytically or reductively is very large: The N-benzyl group
can be cleaved easily with hydrogen/Pd-C [W. H. Hartung and R.
Simonoff, Org. Reactions VII, 263 (1953)], which also applies for
the trityl group [L. Zervas, et al., J. Am. Chem. Soc., 78:1359
(1956)] and the benzyloxycarbonyl group [M. Bergmann and L. Zervas
Ber. 65:1192 (1932)].
[0037] Of the silyl derivatives, the easily cleavable
tert-butyldiphenylsilyl compounds [L. E. Overman et al.,
Tetrahedron Lett., 27:4391 (1986)] and the 2-(trimethylsilyl)-ethyl
carbamates [L. Grehn et al., Angew. Chem. Int. Ed. Engl., 23:296
(1983)] and the 2-trimethylsilylethanesulfonamides [R. S.
Garigipati and S. M. Weinreb, J. Org. Chem., 53:4134 (1988)] are
used, which can be cleaved with fluoride ions. Especially easily
cleavable is the 9-fluorenylmethyl-carba- mate: The cleavage is
carried out with amines such as piperidine, morpholine,
4-dimethylaminopyridine, but also with tetrabutylammonium fluoride
[L. A. Corpino et al., J. Org. Chem., 55:1673 (1990); M. Ueki and
M. Amemiya, Tetrahedron Lett., 28:6617 (1987)].
[0038] The isolation of the end product of general formula I (amine
or carboxylic acid) that is obtained is also carried out according
to methods that are commonly used and well known to one skilled in
the art.
[0039] Thus, for example, in the case of the acid protective group,
the solvent is evaporated from the hydrolysis reaction, and the
residue is taken up in an aprotic solvent. By acidification with an
aqueous acid solution, the pH is set at about 2-4, and then the
organic phase is separated. Using crystallization or
chromatography, the peracylated 1-O-glycoside can now be
obtained.
[0040] The compounds of general formula I that are obtained
optionally also can be converted into their salts in the usual
way.
[0041] The yields of the compounds of general formula I, which can
be achieved with the process according to the invention, are good.
For known compounds in which a comparison with the prior art is
possible, they exceed the yields of the prior art. Thus, for
example, (WO 96/35700), in the reaction of acetobromoglucose with
glycolic acid methyl ester under the influence of mercury oxide and
mercury(II) bromide according to Koenigs-Knorr, the
1-O-methyloxycarbonylmethyl-2,3,4,6-tetra-O-acetyl-glu- copyranose
is obtained with a yield of 60%. The saponification to the free
acid would be connected with a further loss in yield. EP 882733
also describes the production of this compound, but without yield
information. According to the process of the invention, the acid is
also obtained in a two-stage process. Here, the yield is 78%,
however (Example 24 of this application).
[0042] The corresponding
benzyloxycarbonylmethyl-2,3,4,6-O-tetraacetyl-gal- actopyranose is
described in JP 6-271597.
[0043] In addition to the high yields, the process according to the
invention also offers the advantage that it starts from economical
starting materials, makes possible a scale-up of the process, and
allows an easy isolation of the end products.
[0044] The starting materials are commercially available products
or can be obtained easily from commercially available precursors.
Tetra-2,3,4,6-O-acetyl-D-glucopyranose thus can be easily obtained
from the pentaacetyl compound by partial hydrolysis with
benzylamine (Organikum, 4th Edition, VEB Deutscher Verlag der
Wissenschaften Berlin 1964, p. 376). In the case of Fluka,
methyl-D-manno-pyranoside and methyl-D-galactopyranoside are
catalog items. By acylation and cleavage of the glycoside,
2,3,4,6-tetra-O-acyl-D-mannose or -galactose can be obtained.
[0045] The peracyl-1-OH derivatives of the pentoses (ribose,
arabinose), hexoses and deoxyhexoses (rhamnose, fucose) can be
obtained via the sequence of
methylglycoside-peracyl-methylglycoside-peracyl-1-OH-sacchari-
de.
[0046] The compounds that are produced according to the invention
are valuable intermediate products in synthetic chemistry. They can
thus be used, for example, in the synthesis of carbohydrate
dendrimers, for synthesis of NMR contrast media and for introducing
sugar radicals into pharmaceutical agents.
[0047] The process according to the invention is to be explained in
more detail below in the embodiments.
[0048] The entire disclosures of all applications, patents and
publications, cited herein and of corresponding German application
No. 10135098.8, filed Jul. 11, 2001, and U.S. Provisional
Application Serial No. 60/305,876, filed Jul. 18, 2001, are
incorporated by reference herein.
[0049] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0050] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius and, all
parts and percentages are by weight, unless otherwise
indicated.
EXAMPLE 1
[0051] 2,3,4,6-Tetra-O-acetyl-1-O-carboxymethyl-mannopyranose
[0052] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-mannopyranose, 1.70 g (5 mmol) of
tetrabutylammonium hydrogen sulfate and 82.93 g (600 mmol) of
fine-powder potassium carbonate in 350 ml of dioxane is cooled to
0.degree. C. At 0.degree. C., 34.36 g (150 mmol) of bromoacetic
acid benzyl ester is added in drops over 10 minutes while being
stirred vigorously. It is stirred for one hour at 0.degree. C. 250
ml of MTB (methyl-tert-butyl ether) is added, solid is filtered
out, and the filtrate is evaporated to the dry state in a vacuum.
The residue is taken up in 500 ml of ethanol. 5 g of palladium
(10%) on activated carbon is added thereto and hydrogenated until
no more hydrogen is taken up by the solution. Catalyst is filtered
out, it is rewashed with ethanol, and the combined solutions are
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/nhexane/et- hanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0053] Yield: 34.5 g (85% of theory, over two stages) of a
colorless, viscous oil
[0054] Elementary Analysis:
[0055] Cld: C 47.29 H 5.46
[0056] Fnd: C 47.38 H 5.55
EXAMPLE 2
[0057] 2,3,4,6-Tetra-O-benzoyl-1-O-carboxymethyl-mannopyranose
[0058] A mixture that consists of 59.66 g (100 mmol) of
2,3,4,6-tetra-O-benzoyl-mannopyranose, 1.7 g (5 mmol) of
tetrabutylammonium hydrogen sulfate and 63.59 g (600 mmol) of
fine-powder sodium carbonate in 350 ml of 1,2-dimethoxyethane is
cooled to 0.degree. C. At 0.degree. C., 34.36 g (150 mmol) of
bromoacetic acid benzyl ester is added in drops over 10 minutes
while being stirred vigorously. It is stirred for one hour at
0.degree. C. 250 ml of MTB (methyl-tert-butyl ether) is added,
solid is filtered out, and the filtrate is evaporated to the dry
state in a vacuum. The residue is dissolved in 500 ml of ethanol. 5
g of palladium (10%) on activated carbon is added thereto and
hydrogenated until hydrogen absorption is completed. Then, catalyst
is filtered out, rewashed with ethanol, and the combined solutions
are evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0059] Yield: 53.03 g (81% of theory, over two stages) of a
colorless, viscous oil
[0060] Elementary Analysis:
[0061] Cld: C 66.05 H 4.62
[0062] Fnd: C 66.19 H 4.78
EXAMPLE 3
[0063]
2,3,4,6-Tetra-O-pivaloyl-1-O-(5-carboxypentyl)-mannopyranose
[0064] A mixture that consists of 51.66 g (100 mmol) of
2,3,4,6-tetra-O-pivaloyl-mannopyranose, 0.55 g (5 mmol) of
tetramethylammonium chloride and 82.93 g (600 mmol) of fine-powder
potassium hydroxide in 350 ml of diethylene glycol dimethyl ether
is cooled to 10.degree. C. At 10.degree. C., 35.7 g (150 mmol) of
6-bromohexanoic acid benzyl ester is added in drops within 10
minutes while being stirred vigorously. It is stirred for two hours
at 10.degree. C. 250 ml of MTB (methyl-tert-butyl ether) is added,
solid is filtered out, and the filtrate is evaporated to the dry
state in a vacuum. The residue is taken up in 500 ml of ethanol,
mixed with 5 g of palladium (10%) on activated carbon and
hydrogenated until hydrogen absorption is completed. Catalyst is
filtered out, rewashed with ethanol, and the combined solutions are
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0065] Yield: 49.83 g (79% of theory, over two stages) of a
colorless solid
[0066] Elementary Analysis:
[0067] Cld: C 60.93 H 8.63
[0068] Fnd: C 61.12 H 8.78
EXAMPLE 4
[0069]
2,3,4,6-Tetra-O-acetyl-1-O-(1-phenyl-1-carboxy-eth-2-yl)-mannopyran-
ose
[0070] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-mannopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 35.8 g (110 mmol) of fine-powder
cesium carbonate in 400 ml of dioxane is cooled to 0.degree. C. At
0.degree. C., 47.88 g (150 mmol) of 2-phenyl-3-bromopropionic
acid-benzyl ester, dissolved in 30 ml of dioxane, is added in drops
over 10 minutes while being stirred vigorously. It is stirred for
one hour at 0.degree. C. 250 ml of MTB (methyl-tert-butyl ether) is
added, solid is filtered out, and the filtrate is evaporated to the
dry state in a vacuum. The residue is taken up in 500 ml of
tetrahydrofuran. 5 g of palladium (10%) on activated carbon is
added thereto and hydrogenated until hydrogen absorption is
completed. Then, catalyst is filtered out, it is rewashed with a
little tetrahydrofuran, the organic solutions are combined, and it
is evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexane/e- thanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0071] Yield: 39.22 g (79% of theory, over two stages) of a
colorless solid
[0072] Elementary Analysis:
[0073] Cld: C 55.64 H 5.68
[0074] Fnd: C 55.81 H 5.84
EXAMPLE 5
[0075] 2,3,4,6-Tetra-O-benzoyl-1-O-carboxymethyl-mannopyranose
[0076] A mixture that consists of 59.66 g (100 mmol) of
2,3,4,6-tetra-O-benzoyl-mannopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 15.2 g (110 mmol) of anhydrous
potassium carbonate in 500 ml of dimethylformamide is cooled to
0.degree. C. At 0.degree. C., 36.92 g (200 mmol) of chloroacetic
acid benzyl ester is added in drops over 20 minutes while being
stirred vigorously. It is stirred for one hour at 10.degree. C. 250
ml of methyl-tert-butyl ether is added, the organic phase is
separated, it is filtered and evaporated to the dry state in a
vacuum. The residue is taken up in 500 ml of ethanol and mixed with
5 g of palladium (10%) on activated carbon. It is hydrogenated
until hydrogen absorption is completed. Catalyst is filtered out,
it is rewashed with a little ethanol, and the combined solutions
are evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0077] Yield: 53.82 g (82% of theory, over two stages) of a
colorless, viscous oil
[0078] Elementary Analysis:
[0079] Cld: C 66.05 H 4.62
[0080] Fnd: C 66.21 H 4.73
EXAMPLE 6
[0081]
2,3,4,6-Tetra-O-acetyl-1-O-(4-carboxybutyl)-glucopyranose
[0082] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-glucopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml
of tetrahydrofuran is cooled to 0.degree. C. At 0.degree. C., 54.37
g (150 mmol) of 5-tosyloxy-pentanecarboxylic acid benzyl ester,
dissolved in 40 ml of tetrahydrofuran, is added in drops over 30
minutes while being stirred vigorously. It is stirred for three
hours at 0.degree. C. 300 ml of MTB (methyl-tert-butyl ether) is
added, solid is filtered out, and the filtrate is evaporated to the
dry state in a vacuum. The residue is taken up in 500 ml of
tetrahydrofuran. 5 g of palladium (10%) on activated carbon is
added thereto and hydrogenated until hydrogen absorption is
completed. Then, catalyst is filtered out, it is rewashed with a
little tetrahydrofuran and evaporated to the dry state in a vacuum.
The residue is chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexan- e/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate, and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0083] Yield: 34.98 g (78% of theory, over two stages) of a
colorless solid
[0084] Elementary Analysis:
[0085] Cld: C 50.89 H 6.29
[0086] Fnd: C 51.02 H 6.41
EXAMPLE 7
[0087] 2,3,4,6-Tetra-O-pivaloyl-1-O-carboxymethyl-glucopyranose
[0088] A mixture that consists of 54.1 g (100 mmol) of
2,3,4,6-tetra-O-pivaloyl-glucopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 11.22 g of potassium-t-butoxide
(100 mmol) in 500 ml of dimethylacetamide is cooled to 0.degree. C.
At 0.degree. C., 34.36 g (150 mmol) of bromoacetic acid benzyl
ester is added in drops over 20 minutes while being stirred
vigorously. It is stirred for 0.5 hour at 0.degree. C. 250 toluene
is added, the organic phase is separated, it is filtered, and it is
evaporated to the dry state in a vacuum. The residue is taken up in
400 ml of methanol, mixed with 5 g of palladium (10%) on activated
carbon and hydrogenated until hydrogen absorption is completed.
Catalyst is filtered out, it is rewashed with a little methanol,
and the combined organic solutions are evaporated to the dry state
in a vacuum. The residue is chromatographed on silica gel (mobile
solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5).
The product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0089] Yield: 47.12 g (82% of theory, over two stages) of a
colorless, viscous oil
[0090] Elementary Analysis:
[0091] Cld: C 58.52 H 8.07
[0092] Fnd: C 58.69 H 8.19
EXAMPLE 8
[0093]
2,3,4,6-Tetra-O-acetyl-1-O-(10-carboxydecyl)-glucopyranose
[0094] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetylglucopyranose, 0.55 g (5 mmol) of
tetramethylammonium chloride and 12.42 g (100 mmol) of DBN in 350
ml of benzene is cooled to 0.degree. C. At 0.degree. C., 53.30 g
(150 mmol) of 11-bromoundecanoic acid benzyl ester, dissolved in 50
ml of benzene, is added in drops over 30 minutes while being
stirred vigorously. It is stirred for two hours at 20.degree. C.
250 ml of methyl-tert-butyl ether is added, solid is filtered out,
and the filtrate is evaporated to the dry state in a vacuum. The
residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on
activated carbon is added thereto and hydrogenated until hydrogen
absorption is completed. Catalyst is filtered out, it is rewashed
with a little ethanol, and the combined solutions are evaporated to
the dry state in a vacuum. The residue is chromatographed on silica
gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic
acid=20:5:3:0.5). The product-containing fractions are concentrated
by evaporation, dissolved in 400 ml of ethyl acetate and shaken out
three times with 200 ml of water. Then, the organic phase is
separated and evaporated to the dry state in a vacuum.
[0095] Yield: 41.54 g (78% of theory, over two stages) of a
colorless solid
[0096] Elementary Analysis:
[0097] Cld: C 56.38 H 7.57
[0098] Fnd: C 56.42 H 7.81
EXAMPLE 9
[0099] 2,3,4,6-Tetra-O-acetyl-1-O-carboxymethyl-galactopyranose
[0100] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-mannopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 9.62 g (100 mmol) of
sodium-t-butoxide in 350 ml of dimethyl sulfoxide is cooled to
0.degree. C. At 0.degree. C., 36.92 g (200 mmol) of chloroacetic
acid benzyl ester is added in drops over 20 minutes while being
stirred vigorously. It is stirred for one hour at 10.degree. C. 250
ml of methyl-tert-butyl ether is added, the organic phase is
separated, and it is filtered. The solvent is distilled off in a
vacuum. The residue is taken up in 500 ml of ethanol. 5 g of
palladium (10%) on activated carbon is added thereto and
hydrogenated until hydrogen absorption is completed. Catalyst is
filtered out, it is rewashed with a little ethanol and evaporated
to the dry state in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic
acid=20:5:3:0.5). The product-containing fractions are concentrated
by evaporation, dissolved in 400 ml of ethyl acetate and shaken out
three times with 200 ml of water. Then, the organic phase is
separated and evaporated to the dry state in a vacuum.
[0101] Yield: 33.32 g (82% of theory, over two stages) of a
colorless, viscous oil
[0102] Elementary Analysis:
[0103] Cld: C 47.29 H 5.46
[0104] Fnd: C 47.38 H 5.57
EXAMPLE 10
[0105]
2,3,4,6-Tetra-O-acetyl-1-O-[1-(4-carboxy)-phenyl-prop-3-yl-galactop-
yranose
[0106] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetylgalactopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 67.31 g (600 mmol) of
1,4-diazabicyclo[2.2.2]octane in 300 ml of acetonitrile is cooled
to 10.degree. C. At 10.degree. C., 52.26 g (150 mmol) of
4-(3-methanesulfonyloxy-propyl)-benzoic acid benzyl ester,
dissolved in 50 ml of tetrahydrofuran, is added in drops over 30
minutes while being stirred vigorously. It is stirred for two hours
at 10.degree. C. 300 ml of MTB (methyl-tert-butyl ether) is added,
solid is filtered out, and the filtrate is evaporated to the dry
state in a vacuum. The residue is dissolved in 500 ml of
tetrahydrofuran, and 5 g of palladium (10%) on activated carbon is
added thereto and hydrogenated until hydrogen absorption is
completed. Then, catalyst is filtered out, it is rewashed with a
little tetrahydrofuran, and the combined solutions are evaporated
to the dry state in a vacuum. The residue is chromatographed on
silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic
acid=20:5:3:0.5). The product-containing fractions are concentrated
by evaporation, dissolved in 400 ml of ethyl acetate and shaken out
three times with 200 ml of water. Then, the organic phase is
separated and evaporated to the dry state in a vacuum.
[0107] Yield: 39.31 g (77% of theory, over two stages) of a
colorless solid
[0108] Elementary Analysis:
[0109] Cld: C 56.47 H 5.92
[0110] Fnd: C 56.55 H 6.04
EXAMPLE 11
[0111] 2,3,5-Tri-O-benzoyl-1-O-carboxymethyl-ribofuranose
[0112] A mixture that consists of 46.25 g (100 mmol) of
2,3,5-tri-O-benzoylribofuranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride in 400 ml of methyl-tert-butyl ether,
and 82.93 g (600 mmol) of potassium carbonate is cooled to
0.degree. C. At 0.degree. C., 22.91 g (150 mmol) of bromoacetic
acid benzyl ester is added in drops over 20 minutes while being
stirred vigorously. It is stirred for one hour at 0.degree. C. 500
ml of methyl-tert-butyl ether is added thereto, the organic phase
is separated, and the aqueous phase is extracted twice with 200 ml
of methyl-tert-butyl ether. The solvent of the combined organic
phases is dried on sodium sulfate, dessicant is filtered out and
distilled off in a vacuum. The residue is taken up in 500 ml of
ethanol. 5 g of palladium (10%) on activated carbon is added
thereto, and it is hydrogenated until hydrogen absorption is
completed. Then, catalyst is filtered out, it is rewashed with a
little ethanol and evaporated to the dry state in a vacuum. The
residue is chromatographed on silica gel (mobile solvent:
dichloromethane/nhexane/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 200 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0113] Yield: 42.68 g (82% of theory, over two stages) of a
colorless, viscous oil
[0114] Elementary Analysis:
[0115] Cld: C 64.61 H 4.65
[0116] Fnd: C 64.72 H 4.71
EXAMPLE 12
[0117] 2,3,5-Tri-O-benzoyl-1-O-(1-amino-eth-2-yl)-ribofuranose,
hydrochloride
[0118] A mixture that consists of 42.1 g (100 mmol) of
2,3,5-tri-O-benzoyl-ribofuranose, 3.40 g (10 mmol) of
tetrabutylammonium hydrogen sulfate and 63.94 g (600 mmol) of
fine-powder sodium carbonate in 350 ml of dioxane is cooled to
10.degree. C. At 10.degree. C., 45.63 g (150 mmol) of
N-(2-bromoethyl)-dibenzylamine, dissolved in 100 ml of benzene, is
added in drops over 40 minutes while being stirred vigorously. It
is stirred for three hours at 10.degree. C., then 300 ml of benzene
is added, solid is filtered out, and the filtrate is evaporated to
the dry state in a vacuum. The filtrate residue is dissolved in 500
ml of ethanol, mixed with 5 g of Pearlman's catalyst (20% palladium
on activated carbon) and hydrogenated until hydrogen absorption is
completed. Catalyst is filtered out, it is rewashed with a little
ethanol and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/ethanol- /triethylamine=20:2:0.1). The
product-containing fractions are combined and evaporated to the dry
state in a vacuum. It is taken up in absolute diethyl ether, and
the product precipitates with ethereal hydrochloric acid as a
hydrochloride.
[0119] Yield: 42.27 g (78% of theory, over two stages) of a
colorless solid
[0120] Elementary Analysis:
[0121] Cld: C 62.05 H 5.21 N 2.58 Cl 6.54
[0122] Fnd: C 62.19 H 5.28 N 2.66 Cl 6.47
EXAMPLE 13
[0123]
2,3,4,6-Tetra-O-benzoyl-1-O-(1-amino-prop-3-yl)-galactopyranose,
hydrochloride
[0124] A mixture that consists of 42.1 g (100 mmol) of
2,3,4,6-tetra-O-benzoyl-galactopyranose, 1.7 g (5 mmol) of
tetrabutylammonium hydrogen sulfate and 82.93 g (600 mmol) of
fine-powder potassium carbonate in 350 ml of 1,2-dimethoxyethane is
cooled to 10.degree. C. At 10.degree. C., 47.74 g (150 mmol) of
N-(3-bromopropyl)-dibenzylamine, dissolved in 100 ml of
1,2-dimethoxyethane, is added in drops over 40 minutes while being
stirred vigorously. It is stirred for three hours at 10.degree. C.
300 ml of benzene is added, solid is filtered out, and the filtrate
is evaporated to the dry state in a vacuum. The residue is
dissolved in 500 ml of ethanol, mixed with 5 g of Pearlman's
catalyst and hydrogenated until hydrogen absorption is completed.
Catalyst is filtered out, it is rewashed with a little ethanol and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/ethanol/triethylamine=20:2:0.1). The
product-containing fractions are combined and evaporated to the dry
state in a vacuum. The residue is taken up in absolute diethyl
ether, and the product precipitates by addition of ethereal
hydrochloric acid as hydrochloride.
[0125] Yield: 53.14 g (77% of theory, over two stages) of a
colorless solid
[0126] Elementary Analysis:
[0127] Cld: C 64.39 H 5.26 Cl 5.14 N 2.03
[0128] Fnd: C 64.24 H 5.34 Cl 5.21 N 2.11
EXAMPLE 14
[0129] 2,3,4,6-Tetra-O-acetyl-1-O-(1-amino-hex-6-yl)-mannopyranose,
hydrochloride
[0130] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-mannopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 35.84 g (110 mmol) of cesium
carbonate in 500 ml of dioxane is cooled to 0.degree. C. At
0.degree. C., 60.3 g (150 mmol) of
6-bromohexylamine-N-(9-fluorenylmethoxy-carbonyl) is added in drops
over 30 minutes while being stirred vigorously. It is stirred for
one hour at 0.degree. C. 300 ml of dichloromethane is added, the
organic phase is separated, and it is filtered. It is evaporated to
the dry state in a vacuum, and the residue is taken up in 500 ml of
ethanol, 5 g of palladium (10%) on activated carbon is added
thereto and hydrogenated until hydrogen absorption is completed.
Then, catalyst is filtered out, it is rewashed with a little
ethanol and evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/ethanol/triethylamine=20:2:0.1). The
product-containing fractions are combined and evaporated to the dry
state in a vacuum. The residue is taken up in absolute diethyl
ether and mixed with ethereal hydrochloric acid. The product is
obtained as hydrochloride.
[0131] Yield: 38.23 g (79% of theory, over two stages) of a
colorless solid
[0132] Elementary Analysis:
[0133] Cld: C 49.64 H 7.08 N 2.89 Cl 7.33
[0134] Fnd: C 49.69 H 7.20 N 2.94 Cl 7.48
EXAMPLE 15
[0135] 2,3,4-Tri-O--1-O-(1-amino-but-4-yl)-fucopyranose,
hydrochloride benzoyl
[0136] A mixture that consists of 43.5 g (100 mmol) of
2,3,4-tri-O-benzoyl-6-deoxy-galactopyranose, 1.7 g (5 mmol) of
tetrabutylammonium hydrogen sulfate, and 35.84 g (110 mmol) of
cesium carbonate in 400 ml of dichloromethane is cooled to
0.degree. C. At 10.degree. C., 47.4 g (150 mmol) of
2-(trimethylsilyl)-ethylsulfonic acid-N-(4-bromobutyl)-amide,
dissolved in 100 ml of dichloromethane, is added in drops over 30
minutes while being stirred vigorously. It is stirred for two hours
at 10.degree. C. 600 ml of dichloromethane is added, the organic
phase is separated, and the aqueous phase is extracted twice with
200 ml of dichloromethane. The combined organic phases are dried on
sodium sulfate. Dessicant is filtered out, and the solvent is
distilled off in a vacuum. The residue is taken up in 350 ml of
acetonitrile, and 52.3 g (200 mmol) of tetrabutylammonium fluoride
is added as a monohydrate. It is stirred for three hours at
50.degree. C. The solution is evaporated to the dry state, and the
residue is chromatographed on silica gel (mobile solvent:
dichloromethane/ethanol/tr- iethylamine=20:2:0.1). The
product-containing fractions are combined and evaporated to the dry
state in a vacuum. The residue is dissolved in absolute diethyl
ether and mixed with ethereal hydrochloric acid. The product is
obtained as a hydrochloride.
[0137] Yield: 45.56 g (78% of theory, over two stages) of a
colorless solid
[0138] Elementary Analysis:
[0139] Cld: C 63.75 H 5.87 N 2.40 Cl 6.07
[0140] Fnd: C 63.63 H 5.91 N 2.45 Cl 6.18
EXAMPLE 16
[0141]
2,3,4,6-Tetra-O-pivaloyl-1-O-(3,6,9,12,15-pentaoxa-1-carboxy-hexade-
c-16-yl)-glucopyranose
[0142] A mixture that consists of 51.66 g (100 mmol) of
2,3,4,6-tetra-O-pivaloyl-glucopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 63.59 g (600 mmol) of fine-powder
sodium carbonate in 350 ml of dioxane is cooled to 0.degree. C. At
0.degree. C., 91.37 g (130 mmol) of
17-tosyloxy-3,6,9,12,15-pentaoxaheptadecanoic acid benzyl ester,
dissolved in 100 ml of tetrahydrofuran, is added in drops over 50
minutes while being stirred vigorously. It is stirred for three
hours at 0.degree. C. 300 ml of dichloromethane is added, solid is
filtered out, and the filtrate is evaporated to the dry state in a
vacuum. The residue is taken up in 500 ml of ethanol. 5 g of
palladium (10%) on activated carbon is added thereto and
hydrogenated until hydrogen absorption is completed. Then, catalyst
is suctioned out, it is rewashed with a little ethanol and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent: dichloromethane/n
hexane/ethanol/acetic acid=20:8:5:0.5). The product-containing
fractions are concentrated by evaporation, dissolved in 400 ml of
ethyl acetate and shaken out three times with 200 ml of water.
Then, the organic phase is separated and evaporated to the dry
state in a vacuum.
[0143] Yield: 61.21 g (77% of theory, over two stages) of a
colorless oil
[0144] Elementary Analysis:
[0145] Cld: C 57.42 H 8.37
[0146] Fnd: C 57.56 H 8.29
EXAMPLE 17
[0147]
2,3,4,6-Tetra-O-acetyl-1-O-(1-hydroxy-eth-2-yl)-mannopyranose
[0148] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-mannopyranose, 1.7 g (5 mmol) of
tetrabutylammonium hydrogen sulfate and 82.93 g (600 mmol) of
fine-powder potassium hydroxide in 350 ml of diethoxymethane is
cooled to 0.degree. C. At 0.degree. C., 32.26 g (150 mmol) of
2-benzyloxy-ethylbromide is added in drops over 30 minutes while
being stirred vigorously. It is stirred for two hours at 0.degree.
C. 300 ml of benzene is added, solid is filtered out, and the
filtrate is evaporated to the dry state in a vacuum. The residue is
taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated
carbon is added thereto and hydrogenated until hydrogen absorption
is completed. Then, catalyst is suctioned out, it is rewashed with
a little ethanol and evaporated to the dry state in a vacuum. The
residue is chromatographed on silica gel (mobile solvent:
dichloromethane/nhexane/ethanol=20:8:2). The product-containing
fractions are concentrated by evaporation.
[0149] Yield: 30.60 g (78% of theory, over two stages) of a
colorless, viscous oil
[0150] Elementary Analysis:
[0151] Cld: C 48.98 H 6.17
[0152] Fnd: C 48.84 H 6.03
EXAMPLE 18
[0153] 2,3,4,6-Tetra-O-pivaloyl-1-O-carboxymethyl-mannopyranose
[0154] A mixture that consists of 51.66 g (100 mmol) of
2,3,4,6-tetra-O-pivaloyl-mannopyranose, 0.55 g (5 mmol) of
tetramethylammonium chloride and 82.93 g (600 mmol) of fine-powder
potassium carbonate in 350 ml of diethylene glycol dimethyl ether
is cooled to 10.degree. C. At 10.degree. C., 36.65 g (160 mmol) of
2-bromoacetic acid benzyl ester is added in drops within 10 minutes
while being stirred vigorously. It is stirred for two hours at
10.degree. C. 250 ml of MTB (methyl-tert-butyl ether) is added,
solid is filtered out, and the filtrate is evaporated to the dry
state in a vacuum. The residue is taken up in 500 ml of ethanol,
mixed with 5 g of palladium (10%) on activated carbon and
hydrogenated until hydrogen absorption is completed. Catalyst is
filtered out, it is rewashed with ethanol, and the combined
solutions are evaporated to the dry state in a vacuum. The residue
is chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexane/e- thanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0155] Yield: 45.40 g (79% of theory, over two stages) of a
colorless solid
[0156] Elementary Analysis:
[0157] Cld: C 58.52 H 8.07
[0158] Fnd: C 58.44 H 8.18
EXAMPLE 19
[0159]
2,3,4,6-Tetra-O-acetyl-1-O-(1-phenyl-1-carboxy-eth-2-yl)-mannopyran-
ose
[0160] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-mannopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 35.8 g (110 mmol) of fine-powder
cesium carbonate in 400 ml of dimethyl ether is cooled to 0.degree.
C. At 0.degree. C., 47.88 g (150 mmol) of 2-phenyl-3-bromopropionic
acid benzyl ester, dissolved in 30 ml of dimethyl ether, is added
in drops over 10 minutes while being stirred vigorously. It is
stirred for one hour at 0.degree. C. 250 ml of MTB
(methyl-tert-butyl ether) is added, solid is filtered out, and the
filtrate is evaporated to the dry state in a vacuum. The residue is
taken up in 500 ml of tetrahydrofuran. 5 g of palladium (10%) on
activated carbon is added thereto and hydrogenated until hydrogen
absorption is completed. Then, catalyst is filtered out, it is
rewashed with a little tetrahydrofuran, the organic solutions are
combined and evaporated to the dry state in a vacuum, dried, and
the solvent is distilled off in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0161] Yield: 39.22 g (79% of theory, over two stages) of a
colorless solid
[0162] Elementary Analysis:
[0163] Cld: C 55.64 H 5.68
[0164] Fnd: C 55.81 H 5.84
EXAMPLE 20
[0165] 2,3,4,6-Tetra-O-benzoyl-1-O-carboxymethyl-mannopyranose
[0166] A mixture that consists of 59.66 g (100 mmol) of
2,3,4,6-tetra-0-benzoyl-mannopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 15.2 g (110 mmol) of anhydrous
potassium carbonate in 500 ml of diethoxymethane is cooled to
0.degree. C. At 0.degree. C., 36.92 g (200 mmol of 2-chloroacetic
acid benzyl ester is added in drops over 20 minutes while being
stirred vigorously. It is stirred for one hour at 10.degree. C. 250
ml of methyl-tert-butyl ether is added, the organic phase is
separated, it is filtered and evaporated to the dry state in a
vacuum. The residue is taken up in 500 ml of ethanol and mixed with
5 g of palladium (10%) on activated carbon. It is hydrogenated
until hydrogen absorption is completed. Catalyst is filtered out,
it is rewashed with a little ethanol, and the combined solutions
are evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0167] Yield: 53.82 g (82% of theory, over two stages) of a
colorless, viscous oil
[0168] Elementary Analysis:
[0169] Cld: C 66.05 H 4.62
[0170] Fnd: C 66.21 H 4.73
EXAMPLE 21
[0171] 2,3,4,6-Tetra-O-acetyl-1-O-carboxymethyl-glucopyranose
[0172] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetyl-glucopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 15.22 g (100 mmol) of DBU in 300 ml
of tetrahydrofuran is cooled to 0.degree. C. At 0.degree. C., 34.36
g (150 mmol) of 2-bromoacetic acid benzyl ester, dissolved in 40 ml
of tetrahydrofuran, is added in drops over 30 minutes while being
stirred vigorously. It is stirred for three hours at 0.degree. C.
300 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered
out, and the filtrate is evaporated to the dry state in a vacuum.
The residue is taken up in 500 ml of tetrahydrofuran. 5 g of
palladium (10%) on activated carbon is added thereto and
hydrogenated until hydrogen absorption is completed. Then, catalyst
is filtered out, it is rewashed with a little tetrahydrofuran and
evaporated to the dry state in a vacuum. The residue is
chromatographed on silica gel (mobile solvent:
dichloromethane/n=hexan- e/ethanol/acetic acid=20:5:3:0.5). The
product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0173] Yield: 31.69 g (78% of theory, over two stages) of a
colorless solid
[0174] Elementary Analysis:
[0175] Cld: C 47.29 H 5.46
[0176] Fnd: C 47.22 H 5.61
EXAMPLE 22
[0177] 2,3,4,6-Tetra-O-pivaloyl-1-O-carboxymethyl-glucopyranose
[0178] A mixture that consists of 54.1 g (100 mmol) of
2,3,4,6-tetra-O-pivaloyl-glucopyranose, 1.39 g (5 mmol) of
tetrabutylammonium chloride and 11.22 g of potassium-t-butoxide
(100 mmol) in 500 ml of dimethylacetamide is cooled to 0.degree. C.
At 0.degree. C., 34.36 g (150 mmol) of 2-bromoacetic acid benzyl
ester is added in drops over 20 minutes while being stirred
vigorously. It is stirred for one hour at 0.degree. C. Then, 250 ml
of toluene is added thereto, solid is filtered out, it is
evaporated to the dry state in a vacuum, the residue is taken up in
500 ml of ethanol, mixed with 5 g of palladium (10%) on activated
carbon and hydrogenated until the hydrogen absorption is completed.
Catalyst is filtered out, it is rewashed with a little ethanol and
the combined organic solutions are evaporated to the dry state in a
vacuum. The residue is chromatographed on silica gel (mobile
solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5).
The product-containing fractions are concentrated by evaporation,
dissolved in 400 ml of ethyl acetate and shaken out three times
with 200 ml of water. Then, the organic phase is separated and
evaporated to the dry state in a vacuum.
[0179] Yield: 47.12 g (82% of theory, over two stages) of a
colorless, viscous oil
[0180] Elementary Analysis:
[0181] Cld: C 58.52 H 8.07
[0182] Fnd: C 58.69 H 8.19
EXAMPLE 23
[0183] 2,3,4,6-Tetra-O-acetyl-1-O-carboxymethyl-glucopyranose
[0184] A mixture that consists of 34.83 g (100 mmol) of
2,3,4,6-tetra-O-acetylglucopyranose, 0.55 g (5 mmol) of
tetramethylammonium chloride and 12.42 g (100 mmol) of DBN in 350
ml of benzene is cooled to 0.degree. C. At 0.degree. C., 34.36 g
(150 mmol) of 2-bromoacetic acid benzyl ester, dissolved in 50 ml
of benzene, is added in drops over 30 minutes while being stirred
vigorously. It is stirred for two hours at 20.degree. C. 250 ml of
methyl-tert-butyl ether is added, solid is filtered out, and the
filtrate is evaporated to the dry state in a vacuum. The residue is
taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated
carbon is added thereto, and it is hydrogenated until hydrogen
absorption is completed. Catalyst is filtered out, it is rewashed
with a little ethanol, and the combined solutions are evaporated to
the dry state in a vacuum. The residue is chromatographed on silica
gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic
acid=20:5:3:0.5). The product-containing fractions are concentrated
by evaporation, dissolved in 400 ml of ethyl acetate and shaken out
three times with 200 ml of water. Then, the organic phase is
separated and evaporated to the dry state in a vacuum.
[0185] Yield: 31.69 g (78% of theory, over two stages) of a
colorless solid
[0186] Elementary Analysis:
[0187] Cld: C 47.29 H 5.46
[0188] Fnd: C 47.42 H 5.60
[0189] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0190] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *